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A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Orthopaedics.
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2004 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 13, no 8, 799-805 p.Article in journal (Refereed) Published
Abstract [en]

Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

Place, publisher, year, edition, pages
2004. Vol. 13, no 8, 799-805 p.
Keyword [en]
Adolescent, Adult, Animals, Cattle, Child, Child; Preschool, DNA Mutational Analysis, Female, Guinea Pigs, Humans, Male, Mice, Nerve Growth Factor/*genetics, Pain/*genetics, Pain Insensitivity; Congenital/*genetics, Pedigree, Protein Structure; Secondary, Rats
Identifiers
URN: urn:nbn:se:umu:diva-14121DOI: 10.1093/hmg/ddh096PubMedID: 14976160OAI: oai:DiVA.org:umu-14121DiVA: diva2:153792
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mapping genetic diseases in northern Sweden
Open this publication in new window or tab >>Mapping genetic diseases in northern Sweden
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The population of northern Sweden has previously been shown to be well suited for the mapping of monogenic diseases. In this thesis we have tested the hypothesis that this population could also be used for efficient identification of risk genes for common diseases. In Paper I we have hypothesised that despite the admixture of Swedish, Finnish and Sami, the northern Swedish population consists of sub-populations geographically restricted by the main river valleys running through the region. This geographic isolation, in combination with founder effects and genetic drift, could represent a unique resource for genetic studies. On the other hand, it also underlines the importance of accounting for this e.g. in genetic association studies. To test this hypothesis, we studied the patterns of marriage within and between river valley regions and compared allelic frequencies of genetic markers between these regions. The tendency to find a spouse and live in the river valley where one was born is strong, and allelic frequencies of genetic markers vary significantly between adjacent regions. These data support our hypothesis that the river valleys are home to distinct sub-populations and that this is likely to affect mapping of genetic diseases in these populations. In Paper II, we tested the applicability of the population in mapping HSAN V, a monogenic disease. This disease was identified in only three consanguineous individuals suffering from a severe loss of deep pain perception and an impaired perception of heat. A genome-wide scan combined with sequencing of candidate genes resulted in the identification of a causative point mutation in the nerve growth factor beta (NGFB) gene. In Paper III, a large family with multiple members affected by familial forms of type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis (AITD) was studied. This syndrome was mapped to the IDDM12 region on 2q33, giving positive lodscores when conditioning on HLA haplotype. The linkage to HLA and to the IDDM12 region thus confirmed previous reports of linkage and/or association of T1DM and AITD to these loci and provided evidence that the same genetic factors may be mediating these diseases. This also supported the feasibility of mapping complex diseases in northern Sweden by the use of familial forms of these diseases. In Paper IV, we applied the same approach to study type 2 diabetes mellitus (T2DM). A non-parametric genome-wide scan was carried out on a family material from northern Sweden, and linkage was found to the calpain-10 locus, a previously described T2DM-susceptibility gene on 2q37. Together, these findings demonstrate that selecting for familial forms of even complex diseases, and choosing families from the same geographical region can efficiently reduce the genetic heterogeneity of the disease and facilitate the identification of risk genes for the disease.

Publisher
38 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 946
Keyword
Genetics, isolated populations, linkage disequilibrium, linkage analysis, genome-wide scan, hereditary sensory and autonomic neuropathy, type 1 diabetes mellitus, type 2 diabetes mellitus, autoimmune thyroid disease, Genetik
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-499 (URN)91-7305-836-X (ISBN)
Public defence
2005-05-13, A5, 6A, Umeå University, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2005-04-15 Created: 2005-04-15 Last updated: 2009-10-12Bibliographically approved
2. Norrbottnian congenital insensitivity to pain
Open this publication in new window or tab >>Norrbottnian congenital insensitivity to pain
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Congenital insensitivity to pain is a rare hereditary neuropathy. We present patients from a large family in Norrbotten, Sweden with a mutation in the nerve growth factor β gene (NGFß). Using a model of recessive inheritance, we identified an 8.3-Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of candidate genes in the disease-critical region revealed a mutation in the coding region of the NGFß gene specific for the disease haplotype. All three severely affected individuals were homozygous for the mutation. The disease haplotype was also observed in both unaffected and mildly affected family members, but in heterozygote form. We have identified 43 patients, 3 homozygous and 40 heterozygous. The homozygous patients have a severe congenital form with onset of symptoms at an early age, most often affecting the lower extremities with insidious progressive joint swellings or painless fractures. Fracture healing was normal, but the arthropathy was progressive, resulting in disabling Charcot joints with gross deformity and instability. These patients lacked deep pain perception in bones and joints and had no protective reflexes, leading to gross bone and joint complications. They also had abnormal temperature perception but normal ability to sweat. There was no mental retardation. Clinically, they fit best into the group HSAN type V. Sural nerve biopsies showed a moderate loss of thin myelinated fibers (Ad-fibers) and a severe reduction of unmyelinated fibers (C-fibers). 14 of the 40 heterozygous adult patients had mild or moderate problems with joint deformities, usually with only slight discomfort. Treatment was conservative with (if needed) different kinds of orthosis and in some cases joint replacement. Three patients had only neuropathy, and 16 patients had no symptoms.

In congenital disorders like these, it is important to evaluate the age and also the slowly progressive nature, when considering treatment. There is an increased risk of growth disturbances in the very young. The orthopedic operations should therefore be planned from a long-term point of view, but patient education and orthosis are cornerstones in the treatment—to delay the development of neuropathic arthropathy. Arthrodesis, limb lengthening and spinal decompression with fusions are the only elective procedures that seem reasonable.

This Norrbottnian disease is also interesting as a model system for the study of pain.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap, 2006. 32 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1020
Keyword
Pain insensitivity, HSAN
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-746 (URN)91-7264-057-X (ISBN)
Public defence
2006-04-28, Betula, 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-18Bibliographically approved
3. Genetics of pain: studies of migraine and pain insensitivity
Open this publication in new window or tab >>Genetics of pain: studies of migraine and pain insensitivity
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pain is a major public health issue throughout the world. Increased understanding of the different forms of pain and identification of susceptibility genes could contribute to improved treatments. The main aims of this thesis were to identify the underlying genetic causes of pain by studying two large families affected with migraine and pain insensitivity, respectively.

Migraine is one of the most common neurovascular disorders, affecting over 12% of the western population. The genetic contribution to migraine is about 50% according to family and twin studies. To identify novel susceptibility loci for migraine, we performed a genome-wide screen in a large family with migraine from northern Sweden. Linkage analysis revealed significant evidence of linkage (LOD=5.41) on chromosome 6p12.2-p21.1. A predisposing haplotype spanning 10 Mb was inherited with migraine in all affected members of the pedigree. Further fine-mapping of multiple SNP markers restricted the disease critical region to 8.5 Mb. Nine candidate genes were sequenced, revealing no disease-associated polymorphisms in SLC29A1, CLIC5, PLA2G7, IL17, SLC25A27 and TNFRSF21, but rare novel polymorphisms segregating with the disease haplotype in EFHC1, RHAG and MEP1A. EFHC1 has recently been shown to be involved in epilepsy, which is interesting considering the link between migraine and epilepsy. However, association analysis of EFHC1 revealed no difference between patients and controls, suggesting that this gene is not a risk factor for migraine. The combination of the two polymorphisms in RHAG and MEP1A could, however, not be found in any control individuals, indicating that they might be involved in genetic predisposition to migraine in this family.

Disorders with reduced pain sensitivity are very rare, since pain perception is essential for survival. A number of disorders have still been identified with pain insensitivity and peripheral nerve degeneration as major clinical signs, including the hereditary sensory and autonomic neuropathies (HSAN). In order to identify novel susceptibility genes for HSAN V, we performed a genome-wide screen in a large consanguineous pedigree from a small village in northern Sweden. A homozygous region identical-by-descent was identified on chromosome 1p11.2-p13.2 in the three most severely affected patients. Subsequent analysis of candidate genes revealed a missense mutation in a conserved region of the nerve growth factor beta (NGFB) gene, causing a drastic amino acid change (R211W) in the NGF protein. NGF is important for the development and maintenance of the sympathetic and sensory nervous system and is therefore likely to be involved in disease. Functional analysis revealed that mutant NGF failed to induce neurite outgrowth and cell differentiation in PC12 cells. Furthermore, almost no mutant NGF was secreted by COS-7 cells, indicating that the processing and/or secretion of the protein might be disrupted.

In conclusion, these findings present a novel migraine locus on chromosome 6 and identification of two rare polymorphisms that might be risk factors for migraine. Furthermore, a mutation in NGFB was found to cause complete loss of deep pain perception, which represents a very interesting model system to study pain mechanisms.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2006. 70 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1021
Keyword
Migraine, pain insensitivity, susceptibility genes, genome-wide scan, linkage, polymorphism, association, HSAN V, nerve growth factor, neurite outgrowth
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-776 (URN)91-7264-062-6 (ISBN)
Public defence
2006-05-19, Major Groove, 6L, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2006-04-27 Created: 2006-04-27 Last updated: 2009-10-26Bibliographically approved

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